BACKGROUND: There are no available clinical tests that can accurately predict peanut allergy (PA) and/or anaphylaxis. This study is aimed at evaluating whether the component-resolved diagnostic (CRD) IgE and IgG4 tests can (i) distinguish PA from asymptomatic peanut sensitization (PS) and (ii) differentiate anaphylactic from nonanaphylactic PA. METHODS: This study included 20 nonatopic controls, 58 asymptomatically peanut-sensitized children, 55 nonanaphylactic, and 53 anaphylactic PA cases from the Chicago Food Allergy Study. IgE and IgG4 to 103 allergens were measured using the ImmunoCAP ISAC technology and were compared among each group of children. The random forest test was applied to estimate each allergen's ability to predict PA and/or peanut anaphylaxis. RESULTS: Peanut allergy cases (with or without anaphylaxis) had significantly higher IgE reactivity to Ara h 1-3 (peanut allergens) and Gly m 5-6 (soy allergens) than asymptomatically sensitized children (P < 0.00001). Similar but more modest relationships were found for IgG4 to Ara h 2 (P < 0.01). IgE to Ara h 2 was the major contributor to accurate discrimination between PA and asymptomatic sensitization. With an optimal cutoff point of 0.65 ISU-E, it conferred 99.1% sensitivity, 98.3% specificity, and a 1.2% misclassification rate in the prediction of PA, which represented a higher discriminative accuracy than IgE to whole peanut extract (P = 0.008). However, none of the IgE and/or IgG4 tests could significantly differentiate peanut anaphylaxis from nonanaphylactic PA. CONCLUSIONS: IgE to Ara h 2 can efficiently differentiate clinical PA from asymptomatic PS, which may represent a major step forward in the diagnosis of PA.